The invention relates to new leukotriene-B4 derivatives, process for their production and their use as pharmaceutical agents. The new compounds are optically active structural analogs of previously known leukotriene-B4 antagonists, which contain a six-membered ring as a basic structural element (DE 39 17 597, DE 42 27 790, DE 42 42 390). 
KEY
Arachidonsxc3xa4ure=arachidonic acid
Leukotrien A4 (LTA4)=leukotriene A4 (LTA4)
Glutathion-S-transferase=glutathione-S-transferase
Leukotrien B4 (LTB4)=leukotriene B4 (LTB4)
Leukotrien C4 (LTC4)=leukotriene C4 (LTC4)
Leukotriene B4 (LTB4) was discovered by B. Samuelsson et al. as a metabolite of the arachidonic acid. In the biosynthesis, leukotriene A4 is formed by the enzyme 5-lipoxygenase first as a central intermediate product, which then is converted by a specific hydrolase into the LTB4.
The nomenclature of the leukotrienes can be deduced from the following works:
a) B. Samuelsson et al., Prostaglandins 19, 654 (1980); 17, 785 (1979);
b) C. N. Serhan et al., Prostaglandins 34, 201 (1987).
The physiological and especially the pathophysiological importance of leukotriene B4 is summarized in several more recent works: a) The Leukotrienes, Chemistry and Biology eds. L. W. Chakrin, D. M. Bailey, Academic Press 1984. b) J. W. Gillard et al., Drugs of the Future 12, 453 (1987). c) B. Samuelsson, Sciences 237, 1171 (1987). d) C. W. Parker, Drug Development Research 10, 277 (1987). e) W. R. Henderson, Annals of Internal Medicine 121, 684 (1994). It follows from the above that LTB4 is an important inflammation mediator for inflammatory diseases, in which leukocytes invade the affected tissue.
The effects of LTB4 are triggered on the cellular plane by the binding of LTB4 to a specific receptor.
It is known concerning LTB4 that it causes the adhesion of leukocytes to the blood vessel wall. LTB4 is chemotactically active, i.e., it triggers a directed migration of leukocytes in the direction of a gradient of increasing concentration. Furthermore, it indirectly changes the vascular permeability based on its chemotactic activity, whereby a synergism with prostaglandin E2 is observed. LTB4 obviously plays a decisive role in inflammatory, allergic and immunological processes.
Leukotrienes and especially LTB4 are involved in skin diseases, which are accompanied by inflammatory processes (increased vascular permeability and formation of edemas, cell infiltration), increased proliferation of skin cells and itching, such as, for example, in eczemas, erythemas, psoriasis, pruritus and acne. Pathologically increased leukotriene concentrations are involved either causally in the development of many dermatitides or there is a connection between the persistence of the dermatitides and the leukotrienes. Clearly increased leukotriene concentrations were measured, for example, in the skin of patients with psoriasis, atopic dermatitis, allergic contact dermatitis, bullous pemiphigoids, delayed duchurticaria and allergic vasculitis.
Leukotrienes and especially LTB4 are also involved in the diseases of internal organs, for which an acute or chronic inflammatory component was described, e.g.: joint diseases (rheumatic arthritis); diseases of the respiratory tract (asthma and chronically obstructive lung diseases (OPD)); inflammatory intestinal diseases (ulcerous colitis and Crohn""s disease); as well as reperfusion damages (to the heart, intestinal or renal tissues), which result by the temporary pathological obstruction of blood vessels, such as glomerulonephritis, NSAID gastropathies, multiple sclerosis, rhinitis and inflammatory eye diseases.
Further, leukotrienes and especially LTB4 are involved in the disease of multiple sclerosis and in the clinical appearance of shock (triggered by infections, burns or in complications in kidney dialysis or other separately discussed perfusion techniques).
In addition, leukotrienes and especially LTB4 have an effect on the formation of white blood cells in the bone marrow, on the growth of unstriped muscle cells, of keratinocytes and of B-lymphocytes. LTB4 is therefore involved in diseases with inflammatory processes and in diseases with pathologically increased formation and growth of cells.
For example, leukemia or arteriosclerosis represent diseases with this clinical appearance.
Leukotrienes and especially LTB4 and its derivatives are suitable for reducing elevated triglyceride levels and thus act in an anti-arteriosclerotic manner and against obesity.
By the antagonizing of the effects, especially by LTB4, the active ingredients and their forms for dispensing of this invention are specific medicines for diseases of humans and animals, in which especially leukotrienes play a pathological role.
Besides the therapeutic possibilities, which can be derived from an antagonizing of LTB4 action with LTB4 analogs, the usefulness and potential use of leukotriene-B4 agonists for the treatment of fungus diseases of the skin were also able to be shown (H. Katayama, Prostaglandins 34, 797 (1988)).
The invention relates to leukotriene-B4 derivatives of general formula I 
in which
R1 represents CH2OH, CH3, CF3, COOR4, CONR5R6 and
R2 represents H or an organic acid radical with 1-15 C atoms,
R3 symbolizes H; C1-C14 alkyl, C3-C10 cycloalkyl optionally substituted in one or more places; C6-C10 aryl radicals, independently of one another, optionally substituted in one or more places by halogen, phenyl, C1-C4 alkyl, C1-C4 alkoxy, fluoromethyl, chloromethyl, trifluoromethyl, carbonyl, carboxyl or hydroxy; or a 5- to 6-membered aromatic heterocyclic ring with at least 1 heteroatom,
R4 means hydrogen, C1-C10 alkyl, C3-C10 cycloalkyl, C6-C10 aryl radicals optionally substituted by 1-3 halogen, phenyl, C1-C4 alkyl, C1-C4 alkoxy, fluoromethyl, chloromethyl, trifluoromethyl, carboxyl or hydroxy; CH2xe2x80x94COxe2x80x94(C6-C10) aryl or a 5- to 6-membered ring with at least 1 heteroatom;
A symbolizes a trans, transxe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CH, a xe2x80x94CH2CH2xe2x80x94CHxe2x95x90CHxe2x80x94or a tetramethylene group;
B symbolizes a C1-C10 straight-chain or branched-chain alkylene group, which optionally can be substituted by fluorine or the group 
D can mean a direct bond, oxygen, sulfur, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CHxe2x95x90CR7 or together with B can also mean a direct bond;
r5 and R6 are the same or different, and represent H or C1-C4 alkyl optionally substituted by hydroxy groups, or R6 represents H and R5 represents C1-C15 alkanoyl or R8SO2,
R7 means H, C1-C5 alkyl, chlorine, bromine,
R8 has the same meaning as R3,
m means 1-3,
o means 0-5,
p means 0-5,
x is a direct bond, oxygen, sulfur,
y is a C1-C8 alkyl optionally substituted in one or more places, C3-C10 cycloalkyl, and
n is 2-5, and, if R4 means hydrogen, their salts with physiologically compatible bases and their cyclodextrin clathrates.
The group OR2 can be in xcex1- or xcex2-position. Formula I comprises both racemates and the possible pure diastereomers and enantiomers.
As alkyl groups R4, straight-chain or branched-chain alkyl groups with 1-10 C atoms are considered, such as, for example, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, heptyl, decyl.
Alkyl groups R4 can optionally be substituted in one or more places by halogen atoms, alkoxy groups, optionally substituted aryl or aroyl groups with 6-10 C atoms (relative to possible substituents, see under aryl R4), dialkylamino and trialkylammonium with 1-4 C atoms in the alkyl portion, whereby single substitution is to be preferred. As substituents, for example, fluorine, chlorine or bromine, phenyl, dimethylamino, diethylamino, methoxy, ethoxy can be mentioned. As preferred alkyl groups R4, those with 1-4 C atoms can be mentioned.
Cycloalkyl group R4 can contain 3-10, preferably 5 and 6 carbon atoms in the ring. The rings can be substituted by alkyl groups with 1-4 carbon atoms. For example, cyclopentyl, cyclohexyl, methylcyclohexyl can be mentioned.
As aryl groups R4, both substituted and unsubstituted aryl groups with 6-10 C atoms are considered, such as, for example, phenyl, 1-naphthyl and 2-naphthyl, which can be substituted in each case by 1-3 halogen atoms (F, Cl, Br), a phenyl group, 1-3 alkyl groups with, in each case, 1-4 C atoms, a chloromethyl, a fluoromethyl, trifluoromethyl, carboxyl, hydroxy or alkoxy group with 1-4 C atoms. Preferred substituents in 3- and 4-position on the phenyl ring are, for example, fluorine, chlorine, alkoxy or trifluoromethyl, in 4-position, however, hydroxy.
As heterocyclic groups R4, 5- and 6-membered aromatic heterocycles that contain at least 1 heteroatom, preferably nitrogen, oxygen or sulfur, are suitable. For example, 2-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, oxazolyl, thiazolyl, pyrimidinyl, pyridazinyl, 3-furyl, 3-thienyl, 2-tetrazolyl, i.a., can be mentioned.
As acid radical R5, such physiologically compatible acids are suitable. Preferred acids are organic carboxylic acids and sulfonic acids with 1-15 carbon atoms, which belong to the aliphatic, cycloaliphatic, aromatic, aromatic-aliphatic and heterocyclic series. These acids can be saturated, unsaturated and/or polybasic and/or substituted in the usual way. As examples of the substituents, C1-4 alkyl, hydroxy, C1-4 alkoxy, oxo or amino groups or halogen atoms (F, Cl, Br) can be mentioned. For example, the following carboxylic acids can be mentioned: formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, trimethylacetic acid, diethylacetic acid, tert-butylacetic acid, cyclopropylacetic acid, cyclopentylacetic acid, cyclohexylacetic acid, cyclopropanecarboxylic acid, cyclohexanecarboxylic acid, phenylacetic acid, phenoxyacetic acid, methoxyacetic acid, ethoxyacetic acid, mono-, di- and trichloroacetic acid, aminoacetic acid, diethylaminoacetic acid, piperidinoacetic acid, morpholinoacetic acid, lactic acid, succinic acid, adipic acid, benzoic acid; benzoic acids substituted with halogen (F, Cl, Br) or trifluoromethyl, hydroxy, C1-4 alkoxy or carboxy groups; nicotinic acid, isonicotinic acid, furan-2-carboxylic acid, cyclopentylpropionic acid. As preferred arylsulfonyl radicals and alkanesulfonyl radicals R8SO2, those are to be considered that are derived from a sulfonic acid with up to 10 carbon atoms. As sulfonic acids, for example, methanesulfonic acid, ethanesulfonic acid, isopropanesulfonic acid, cyclohexanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-chlorobenzenesulfonic acid, N,N-dimethylaminosulfonic acid, N,N-diisobutylaminosulfonic acid, N,N-dibutylaminosulfonic acid, pyrrolidino, piperidino, piperazino, M-methylpiperazino and morpholinosulfonic acid are suitable.
As alkyl groups R3, straight-chain and branched-chain, saturated and unsaturated alkyl radicals, preferably saturated, with 1-14, especially 1-10 C atoms, are suitable, which optionally can be substituted by optionally substituted phenyl (for substitution, see under aryl R5). For example, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, butenyl, isobutenyl, propenyl, pentenyl, benzyl, m- and p-chlorobenzyl groups can be mentioned. If alkyl groups R3 are halogen-substituted, fluorine, chlorine and bromine are suitable as halogens.
As examples of halogen-substituted alkyl groups R3, alkyls with terminal trifluoromethyl groups are considered.
Cycloalkyl group R3 can contain 3-10, preferably 3-6 carbon atoms in the ring. The rings can be substituted by alkyl groups with 1-4 carbon atoms optionally by halogens. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl-cyclohexyl, fluorocyclohexyl can be mentioned.
As substituted or unsubstituted aryl groups R3, for example, phenyl, 1-naphthyl and 2-naphthyl, which can be substituted in each case by 1-3 halogen atoms (F, Cl, Br), a phenyl group, 1-3 alkyl groups with 1-4 C atoms in each case, a chloromethyl, fluoromethyl, trifluoromethyl, carboxyl, C1-C4 alkoxy or hydroxy group, are considered. Preferred is the substitution in 3- and 4-position on the phenyl ring by, for example, fluorine, chlorine, alkoxy or trifluoromethyl or in 4-position by hydroxy.
As heterocyclic aromatic groups R3, 5- and 6-membered heterocycles that contain at least 1 heteroatom, preferably nitrogen, oxygen or sulfur, are suitable. For example, 2-furyl, 1-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, oxazolyl, thiazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, 3-furyl, 3-thienyl, i.a., can be mentioned.
As alkylene groups B, straight-chain or branched, saturated or unsaturated alkylene radicals, preferably saturated with 1-10, especially with 1-5 C atoms, are suitable, which optionally can be substituted by fluorine atoms. For example, methylene, fluoromethylene, difluoromethylene, ethylene, 1,2-propylene, ethylethylene, trimethylene, tetramethylene, pentamethylene, 1,2-difluoroethylene, 1-fluoroethylene, 1-methyltetramethylene, 1-methyl-trimethylene, 1-methylene-ethylene, 1-methylene-tetramethylene can be mentioned.
In addition, alkylene group B can represent the group 
whereby n=2-5, preferably 3-5.
As acid radicals R2, those of physiologically compatible acid radicals are suitable. Preferred acids are organic carboxylic acids and sulfonic acids with 1-15 carbon atoms, which belong to the aliphatic, cycloaliphatic, aromatic, aromatic-aliphatic or heterocyclic series. These acids can be substituted saturated, unsaturated and/or polybasic and/or in the usual way. As examples of the substituents, C1-4 alkyl, hydroxy, C1-4 alkoxy, oxo or amino groups or halogen atoms (F, Cl, Br) can be mentioned. For example, the following carboxylic acids can be mentioned: formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, trimethylacetic acid, diethylacetic acid, tert-butylacetic acid, cyclopentylacetic acid, cyclohexylacetic acid, cyclohexanecarboxylic acid, phenylacetic acid, phenoxyacetic acid, methoxyacetic acid, ethoxyacetic acid, mono-, di- and trichloroacetic acid, aminoacetic acid, diethylaminoacetic acid, piperidinoacetic acid, morpholinoacetic acid, lactic acid, succinic acid, adipic acid, benzoic acid; benzoic acids substituted with halogen (F, Cl, Br) or trifluoromethyl, hydroxy, C14 alkoxy or carboxy groups; nicotinic acid, isonicotinic acid, furan-2-carboxylic acid, cyclopentylpropionic acid. As preferred acid radicals R2 and R3, those acyl radicals with up to 10 carbon atoms are considered.
Alkyl radicals R5 and R6, which optionally contain hydroxy groups, are straight-chain or branched alkyl radicals, especially straight-chain, such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, especially preferably methyl.
R7 as C1-5 alkyl means straight-chain or branched-chain alkyl radicals as were already mentioned for R3 or R4. Preferred alkyl radicals R7 are methyl, ethyl, propyl and isopropyl.
Inorganic and organic bases are suitable for salt formation, as they are known to one skilled in the art for forming physiologically compatible salts. For example, alkali hydroxides, such as sodium hydroxide and potassium hydroxide, alkaline-earth hydroxides, such as calcium hydroxide, ammonia, amines, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, tris-(hydroxymethyl)-methylamine, etc., can be mentioned.
To attain the cyclodextrin clathrates, the compounds of formula I are reacted with xcex1-, xcex2- or xcex3-cyclodextrin. Preferred are xcex2-cyclodextrin derivatives.
Preferred compounds of this invention are compounds of general formula I, whereby the radicals have the following meaning:
R1 is CH2OH, CONR5R6, COOR4 with R4 in the meaning of a hydrogen atom, an alkyl radical with 1-10 C atoms, a cycloalkyl radical with 5-6 C atoms, a phenal radical optionally substituted by 1-2 chlorine, bromine, phenyl, C1-4 alkyl, C1-4 alkoxy, chloromethyl, fluoromethyl, trifluoromethyl, carboxy or hydroxy,
x is an oxygen atom,
y is a methyl group,
p is 1-3,
o is 1-3,
m is 1-3,
A is a trans-CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94 or a tetramethylene group;
B is a straight-chain or branched-chain saturated or unsaturated alkylene group with up to 10 C atoms, which optionally can be substituted by fluorine or the group 
with n=2-5,
D is a direct bond, oxygen, sulfur, a xe2x80x94Cxe2x89xa1Cxe2x80x94 group or a xe2x80x94CHxe2x95x90CR7 group with R7 as hydrogen, C1-5 alkyl, chlorine or bromine;
B and D together are a direct bond;
R2 means hydrogen or an organic acid radical with 1-15 C atoms;
R5 and R6 have the above-indicated meanings;
R3 is a hydrogen atom, C1-C10 alkyl, cycloalkyl with 5-6 C atoms, a phenyl radical optionally substituted by 1-2 chlorine, bromine, phenyl, C1-4 alkyl, C1-4 alkoxy, chloromethyl, fluoromethyl, trifluoromethyl, carboxy or hydroxy, and if
R4 means a hydrogen, their salts with physiologically compatible bases and their cyclodextrin clathrates.
Especially preferred compounds of this invention are compounds of general formula I, whereby the radicals have the following meaning:
R1 is CH2OH, CONR5R6, COOR4 with R4 in the meaning of a hydrogen atom, an alkyl radical with 1-4 C atoms;
R2 means hydrogen or an organic acid radical with 1-6 C atoms;
R3 is a hydrogen atom or c1-10 alkyl;
R5 and R6 have the above-indicated meanings;
A is a trans, trans-CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94 or tetramethylene group;
B is a straight-chain or branched-chain alkylene group with up to 5 C atoms, or the group 
with n=3,4;
D is a direct bond or a xe2x80x94Cxe2x89xa1C group or a xe2x80x94CHxe2x95x90CR7 group with R7 as hydrogen or C1-5 alkyl;
x is an oxygen atom,
y is a methyl group,
p is 1,
o is 1,
m is 1, 2;
B and D are together a direct bond;
and if R4 means a hydrogen atom, their salts with physiologically compatible bases and their cyclodextrin clathrates.
In addition, the invention relates to a process for the production of the compounds of general formula I according to the invention, which is characterized in that a ketone of formula II, 
in which A, B, D, R2, R3 and Y have the above-indicated meaning, optionally under protection of free hydroxy groups in R2, is reacted with an olefination reagent of general formula III,
Exe2x80x94(CH2)xe2x80x94(CH2)oxe2x80x94Xxe2x80x94(CH2)pxe2x80x94R1xe2x80x83xe2x80x83(III)
whereby E represents a 
or 
or 
radical, and o, X, p, and R1 have the above-indicated meanings, is reacted in the presence of a base and optionally then separated in any sequence of isomers, protected hydroxy groups are released and/or a free hydroxy group is etherified and/or the 1-hydroxy group is oxidized to carboxylic acid and/or reduced and/or a carboxyl group is esterified and/or a free carboxyl group is converted into an amide or a carboxyl group is converted into a salt with a physiologically compatible base.
The reaction of the compound of general formula II with an olefination reagent of general formula III is performed in the presence of a base at temperatures of xe2x88x9280xc2x0 C. to 100xc2x0 C., preferably xe2x88x9220xc2x0 C. to 80xc2x0 C. in an aprotic solvent or solvent mixture, for example tetrahydrofuran, diethyl ether, dimethyl sulfoxide. As bases, depending on the meaning of radical E, sodium hydride, methylsulfinylmethyl sodium, potassium-tert-butylate, lithium diisopropylamide, 1,5-diazabicyclo[4.3.0]non-5-ene are suitable. The separation of the Z- and E-configured olefines that are obtained in this case is carried out in the usual way, for example by column chromatography.
The reduction to the compounds of formula I with R1 in the meaning of a CH2OH group is performed with a reducing agent that is suitable for the reduction of esters or carboxylic acids, such as, for example, lithium aluminum hydride, diisobutyl aluminum hydride, etc. As solvents, diethyl ether, tetrahydrofuran, dimethoxyethane, toluene, etc., are suitable. The reduction is performed at temperatures of xe2x88x9230xc2x0 C. up to boiling temperature of the solvent that is used, preferably 0xc2x0 C. to 30xc2x0 C.
The esterification of the alcohols of formula I (R2xe2x95x90H) is carried out in a way that is known in the art. For example, the esterification is carried out in that an acid derivative, preferably an acid halide or acid anhydride, is reacted with an alcohol of formula I in the presence of a base such as, for example, sodium hydride, pyridine, triethylamine, tributylamine or 4-dimethylaminopyridine. The reaction can be performed without a solvent or in an inert solvent, preferably acetone, acetonitrile, dimethylacetamide, dimethyl sulfoxide at temperatures above or below room temperature, for example, between xe2x88x9280xc2x0 C. to 100xc2x0 C., preferably at room temperature.
The etherification of the alcohols of formula I (R1xe2x95x90CH2OH) is carried out in a way that is known in the art. For example, the etherification is carried out in that the alcohol of general formula I (R1xe2x95x90CH2OH), optionally under protection of present free hydroxy groups with a halocarboxylic acid derivative or haloalkyl derivative of general formula IV,
Halxe2x80x94(CH2)pxe2x80x94R1xe2x80x83xe2x80x83(IV)
whereby Hal is a chlorine, bromine or iodine atom and R1 has the above-indicated meaning, is reacted in the presence of a base, and then optionally R1, as described above, is further functionalized. The reaction of the compound of general formula I with a halogen compound of general formula IV is performed at temperatures of 0xc2x0 C. to 100xc2x0 C., preferably 10xc2x0 C. to 80xc2x0 C., in an aprotic solvent or solvent mixture, for example dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, toluene, etc. As bases, the bases that are known to one skilled in the art for etherification are suitable, for example sodium hydride, potassium-tert-butylate, butyllithium. The above-mentioned etherification can also be performed preferably under phase-transfer conditions with 20-50% aqueous sodium hydroxide or potassium hydroxide solution without an additional solvent or in an aprotic solvent, such as, for example, toluene in the presence of a phase-transfer catalyst such as tetrabutylammonium hydrogen sulfate at temperatures of between 0xc2x0 C. and 90xc2x0 C., preferably between 20xc2x0 C. and 60xc2x0 C.
The oxidation of the 1-hydroxy group is performed according to the methods that are known to one skilled in the art. As oxidizing agents, for example, the following can be used: pyridinium dichromate (Tetrahedron Letters, 1979, 399), Jones reagent (J. Chem. Soc. 1953, 2555) or platinum/oxygen (Adv. in Carbohydrate Chem. 17, 169 (1962) or Collins oxidation (Tetrahedron Letters 1968, 3363) and subsequent Jones oxidation. The oxidation with pyridinium dichromate is performed at temperatures of 0xc2x0 C. to 100xc2x0 C., preferably at 20xc2x0 C. to 40xc2x0 C. in a solvent that is inert with respect to the oxidizing agent, for example dimethylformamide.
The oxidation with Jones reagent is performed at temperatures of xe2x88x9240xc2x0 C. to +40xc2x0 C., preferably 20xc2x0 C. to 30xc2x0 C. in acetone as a solvent.
The oxidation with platinum/oxygen is performed at temperatures of 0xc2x0 C. to 60xc2x0 C., preferably 20xc2x0 C. to 40xc2x0 C. in a solvent that is inert with respect to the oxidizing agent, such as, e.g., ethyl acetate.
The saponification of the esters of formula I is performed according to the methods that are known to one skilled in the art, such as, for example, with basic catalysts. The compounds of formula I can be separated by the conventional separating methods into optical isomers (Asymmetric Synthesis, Vol. 1-5, Ed. J. D. Morrison, Academic Press, Inc., Orlando etc., 1985; Chiral Separations by HPLC, Ed. A. M. Krstulovic; John Wiley and Sons; New York etc. 1989).
The release of the functionally modified hydroxy groups is carried out according to known methods. For example, the cleavage of hydroxy protective groups, such as, for example, the tetrahydropyranyl radical, is performed in an aqueous solution of an organic acid, such as, e.g., oxalic acid, acetic acid, propionic acid, i.a., or in an aqueous solution of an inorganic acid, such as, e.g., hydrochloric acid. To improve the solubility, a water-miscible, inert, organic solvent is suitably added. Suitable organic solvents are, e.g., alcohols, such as methanol and ethanol, and ethers, such as dimethoxyethane, dioxane and tetrahydrofuran. Tetrahydrofuran is preferably used. The cleavage is performed preferably at temperatures of between 20xc2x0 C. and 80xc2x0 C. The cleavage of the silyl ether protective groups is carried out, for example, with tetrabutylammonium fluoride or with potassium fluoride in the presence of a crown ether (such as, for example, dibenzo[18]-crown-6). As a solvent, for example, tetrahydrofuran, diethyl ether, dioxane, dichloromethane, etc., are suitable. The cleavage is performed preferably at temperatures of between 0xc2x0 C. and 80xc2x0 C.
The saponification of the acyl groups is carried out, for example, with alkali or alkaline-earth carbonates or -hydroxides in an alcohol or in the aqueous solution of an alcohol. As an alcohol, lower aliphatic alcohols, such as, e.g., methanol, ethanol, butanol, etc., preferably methanol, are considered. As alkali carbonates and -hydroxides, potassium and sodium salts can be mentioned. Preferred are potassium salts.
As alkaline-earth carbonates and -hydroxides, for example, calcium carbonate, calcium hydroxide and barium carbonate are suitable. The reaction is carried out at xe2x88x9210xc2x0 C. to +70xc2x0 C., preferably at +25xc2x0 C.
The introduction of ester group xe2x80x94COOR4 for R1, in which R4 represents an alkyl group with 1-10 C atoms, is carried out according to the methods that are known to one skilled in the art. The 1-carboxy compounds are reacted, for example, with diazohydrocarbons in a way that is known in the art. The esterification with diazohydrocarbons is carried out, e.g., in that a solution of the diazohydrocarbon in an inert solvent, preferably in diethyl ether, is mixed with the 1-carboxy compound in the same solvent or in another inert solvent, such as, e.g., methylene chloride. After the reaction is completed in 1 to 30 minutes, the solvent is removed, and the ester is purified in the usual way. Diazoalkanes are either known or can be produced according to known methods [Org. Reactions Vol. 8, pages 389-394 (1954)).
The introduction of ester group xe2x80x94COOR4 for R1, in which R4 represents a substituted or unsubstituted aryl group, is carried out according to the methods that are known to one skilled in the art. For example, the 1-carboxy compounds are reacted in an inert solvent with the corresponding arylhydroxy compounds with dicyclohexylcarbodiimide in the presence of a suitable base, for example, pyridine, dimethylaminopyridine, triethylamine. As a solvent, methylene chloride, ethylene chloride, chloroform, ethyl acetate, tetrahydrofuran, preferably chloroform, are suitable. The reaction is performed at temperatures of between xe2x88x9230xc2x0 C. and +50xc2x0 C., preferably at 10xc2x0 C.
If Cxe2x95x90C double bonds that are contained in the primary product are to be reduced, the hydrogenation is carried out according to methods that are known in the art.
The hydrogenation of the xcex948,10-diene system is performed in a way that is known in the art at low temperatures, preferably at about xe2x88x9220xc2x0 C. to +30xc2x0 C. in a hydrogen atmosphere in the presence of a noble metal catalyst. As a catalyst, for example, 10% palladium on carbon is suitable.
The leukotriene-B4 derivatives of formula I with R4 meaning a hydrogen can be converted into a salt with suitable amounts of the corresponding inorganic bases with neutralization. For example, in dissolving the corresponding acids in water, which contains the stoichiometric amount of the base, the solid inorganic salt is obtained after water is evaporated or after a water-miscible solvent, e.g., alcohol or acetone, is added.
For the production of an amino salt, LTB4-acid is dissolved in, e.g., a suitable solvent, for example, ethanol, acetone, diethyl ether, acetonitrile or benzene, and at least the stoichiometric amount of the amine is added to the solution. In this way, the salt usually accumulates in solid form or is isolated after the solvent is evaporated in the usual way.
The introduction of amide group xe2x80x94CONHR5 with R5 in the meaning of alkanoyl is carried out according to the methods that are known to one skilled in the art. The carboxylic acids of formula I (R4xe2x95x90H) are first converted into the mixed anhydride in the presence of a tertiary amine, such as, for example, triethylamine, with isobutyl chloroformate. The reaction of the mixed anhydride with the alkali salt of the corresponding amide or with ammonia (R5xe2x95x90H) is carried out in an inert solvent or solvent mixture, such as, for example, tetrahydrofuran, dimethoxyethane, dimethylformamide, hexamethylphosphoric acid triamide, at temperatures of between xe2x88x9230xc2x0 C. and +60xc2x0 C., preferably at 0xc2x0 C. to 30xc2x0 C. Another type of production of the amides involves the amidolysis of 1-ester (R1xe2x95x90COOR4) with the corresponding amine.
Another possibility for the introduction of amide group xe2x80x94CONHR5 consists in the reaction of a 1-carboxylic acid of formula I (R4xe2x95x90H), in which free hydroxy groups are optionally intermediately protected, with compounds of formula IV,
Oxe2x95x90Cxe2x95x90Nxe2x80x94R5xe2x80x83xe2x80x83(IV)
in which R5 has the above-indicated meaning.
The reaction of the compound of formula I (R4xe2x95x90H) with an isocyanate of formula IV is carried out optionally with the addition of a tertiary amine, such as, e.g., triethylamine or pyridine. The reaction can be performed without a solvent or in an inert solvent, preferably acetonitrile, tetrahydrofuran, acetone, dimethylacetamide, methylene chloride, diethyl ether, toluene, at temperatures of between xe2x88x9280xc2x0 C. to 100xc2x0 C., preferably at 0xc2x0 C. to 30xc2x0 C.
For the production of the other amides, for example, the desired acid anhydride can be reacted with ammonia or the corresponding amines.
If the starting product contains OH groups in the leukotriene-B4 radical, these OH groups are also brought to reaction. If end products that contain free hydroxyl groups are ultimately desired, a start is suitably made from starting products in which the latter are intermediately protected by preferably readily cleavable ether or acyl radicals.
The separation of the diastereomers is carried out according to the methods that are known to one skilled in the art, for example by column chromatography.
The compounds of general formula II that are used as starting material can be produced, for example, by an ester of general formula V ((a) K. Sakai et al., Tetrahedron 50, 3315 (1995); b) K. Koga et al., Tetrahedron 49, 1579 (1993)), 
in which m and Y have the above-indicated meanings, being ketalized with ethylene glycol, reduced with diisobutylaluminum hydride and then oxidized to the aldehyde of general formula VI with the Collins reagent or by the Swern process (Tetrahedron Letters 34, 1651 (1978)) in a way that is known in the art. 
The Wittig-Horner olefination of aldehyde VI with the phosphonate of formula VII and a base and optionally subsequent hydrogenation as well as subsequent reduction of the ester group, oxidation of the primary alcohol, repeated Wittig-Horner olefination with the phosphonate of formula VII and optionally subsequent hydrogenation or a Wittig-Horner reaction of aldehyde VI with a phosphonate of formula VIII provides the esters of general formula IX, whereby 
m, y and A have the above-indicated meanings. As bases, for example, potassium-tert-butylate, diazabicyclononane, diazabicycloundecane or sodium hydride are suitable. Reduction of the ester group, for example with diisobutyl aluminum hydride, and subsequent oxidation of the primary alcohol that is obtained, e.g., with manganese dioxide or Collins reagent, results in an aldehyde of formula X. 
The organometallic reaction of the aldehyde of formula X with a Grignard reagent of formula XI, in which B, D
Xxe2x80x94Mgxe2x80x94Bxe2x80x94Dxe2x80x94R3xe2x80x83xe2x80x83(XI)
and R3 have the above-indicated meanings and X means chlorine, bromine or iodine, results, under protection of the hydroxy groups (for example by acylation) and optionally diastereomer separation, in the compounds of formula XII. 
The production of the compound of formula XI that is required for the organometallic reaction is carried out by reaction of the corresponding terminal halide with magnesium. By reaction of ketal XII with dilute acetic acid and optionally saponification of the ester and subsequent silylether formation, the ketone of formula XIII is obtained. 
The compounds of formula XII, in which B means a CH2 group and D means a xe2x80x94Cxe2x89xa1C group or a CHxe2x95x90CR7 group, can be obtained, for example, by an organometallic reaction of a propargyl halide and subsequent alkylation with a corresponding alkyl halide and optionally subsequent Lindlar hydrogenation.
An alternative structure of the lower chain starts from the aldehyde of formula XIV, which resulted from the Wittig-Horner reaction of aldehyde VI and subsequent reduction and oxidation. 
Wittig-Horner olefination of aldehyde XIV with a phosphonate of formula XV 
and reduction of the ketone that is produced then resulted in an alcohol of formula XII, which optionally can be separated into diastereomers. The protection of the hydroxy group that is now added, for example by acylation, ketal cleavage with acetic acid, optionally saponification of the ester and silylether formation results in the ketone of formula XIII.
The production of the phosphonates of general formula XV that are required for this reaction is described in, for example, DE 42 42 390 or is carried out in a way that is known in the art by reaction of an alkyl halide (that can be produced from the corresponding alcohol by halogenation) of general formula XVI
Halxe2x80x94Dxe2x80x94R3xe2x80x83xe2x80x83(XVI)
with the dianion that is produced from the phosphonate of general formula XVII 
in which B, D and R3 have the above-indicated meanings.
An alternative access to the phosphonates of general formula XV consists in the reaction of the anion of methylphosphonic acid dimethyl ester with an ester of general formula XVIII,
R9OOCxe2x80x94Bxe2x80x94Dxe2x80x94R3xe2x80x83xe2x80x83(XVIII)
in which R3, B, and D have the above-indicated meanings and R9 means an alkyl group with 1-5 C atoms. These esters can be obtained by, for example, alkylation with the corresponding halide.
The incorporation of the chemically and metabolically labile cis-xcex946,7 double bond of LTB4 into a cis-1,2-substituted cycloalkyl ring results in a stabilization, whereby especially by further derivatization of the functional groups and/or structural changes of the lower side chain, LTB4 derivatives that can act as LTB4 antagonists were obtained (DE-A 39 17 597 and DE-A 42 27 790.6 and DE-A 41 08 351 and DE-A 41 39 886.8 and DE-A 42 42 390).
It has now been found that by introducing an alkyl group into the 7-position and by introducing a double bond into 5,6-position (numbering system beginning with a carboxyl-C atom with 1 when LTB4 nomenclature is used) in such leukotriene-B4 derivatives, a prolonged duration of action, greater selectivity and better effectiveness can be achieved.
The compounds of formula I act in an antiinflammatory, antiallergic and antiproliferative manner. In addition, the compounds are suitable for lowering elevated triglyceride levels. In addition, they have antimycotic properties. Consequently, the new leukotriene-B4 derivatives of formula I represent valuable pharmaceutical active ingredients. The compounds of formula I are suitable for topical and oral administration.
The new leukotriene-B4 derivatives of formula I are suitable in combination with the additives and vehicles that are commonly used in galenical pharmaceutics for topical treatment of diseases of the skin, in which leukotrienes play an important role, e.g.: contact dermatitis, eczemas of the most varied types, neurodermatoses, erythrodermia, pruritus vulvae et ani, rosacea, cutaneus lupus erythematosus, psoriasis, lichen ruber planus et verrucosis and similar skin diseases.
In addition, the new leukotriene-B4 antagonists are suitable for the treatment of multiple sclerosis and symptoms of shock.
The production of the pharmaceutical agent specialties is carried out in the usual way by the active ingredients being converted with suitable additives into the desired form of administration, such as, for example: solutions, ointments, creams or patches.
In the thus formulated pharmaceutical agents, the active ingredient concentration depends on the form of administration. In lotions and ointments, an active ingredient concentration of 0.0001% to 3% is preferably used.
Further, the new compounds optionally in combination with commonly used vehicles and adjuvants are also well-suited for the production of inhalants, which can be used to treat allergic diseases of the respiratory system, such as, for example, bronchial asthma or rhinitis.
Further, the new leukotriene-B4 derivatives are also suitable in the form of capsules, tablets or coated tablets, which preferably contain 0.1 to 100 mg of active ingredient and are administered orally or in the form of suspensions, which preferably contain 1-200 mg of active ingredient per dosage unit, and are also administered rectally to treat diseases of the internal organs, in which leukotrienes play an important role, such as, e.g.: allergic diseases of the intestinal tract, such as colitis ulcerosa and colitis granulomatosa.
In these new forms of administration, the new LTB4 derivatives, in addition to the treatment of diseases of internal organs with inflammatory processes, are also suitable for the treatment of diseases in which, leukotriene-dependent, the increased growth and the new formation of cells are important. Examples are leukemia (increased growth of white blood cells) or arteriosclerosis (increased growth of smooth muscle cells of blood vessels).
The new leukotriene-B4 derivatives can also be used in combination with, e.g., lipoxygenase inhibitors, cyclooxygenase inhibitors, glucocorticoids, prostacyclin agonists, thromboxane antagonists, leukotriene-D4 antagonists, leukotriene-E4 antagonists, leukotriene-F4 antagonists, phosphodiesterase inhibitors, calcium antagonists, PAF antagonists or other known forms of treatment of the respective diseases.
The following embodiments are used for a more detailed explanation of the process according to the invention. In the examples, diastereomers in 12-position that are not characterized in more detail were characterized as polar or nonpolar (e.g., diastereomer unpol [nonpol] (12)).